1. Field of the Invention
The invention relates to a transdermal therapeutic system for the release of 17-.beta.-estradiol and, optionally, further active substances through the skin to the human body.
2. The Prior Art
Transdermal therapeutic systems (TTS) have already been introduced on the market for the pharmaceutical therapy of a series of deseases. Meanwhile, even TTS comprising the active substance 17-.beta.-estradiol have become available on the market as therapeutic agents for climacteric complaints, recently also for osteoporosis, and they are being successfully applied in therapy.
One disadvantage of the systems according to the prior art is the insufficient capacity of the active substance to permeate the skin, which despite numerous galenic measures aimed at the TTS design (the use of multilayered systems and control membranes, variation of the active substance concentration, modification of the base polymer, etc.) can-not be increased beyond a certain limit, the so-called "saturation flow". The conclusion that the transdermal flow of an active substance out of the solid, finely dispersed phase can in principal not be increased further, not even where more highly solvent vehicles are used, already appears in the works of Higuchi (e.g. T. Higuchi: Physical Chemical Analysis of percutaneous absorption process from creams and ointments. J. Soc. Cosmetic Chem. 11, pages 85-97 (1960), which have been pioneering books to this day.
The systems described in EP 0 421 454 contain 17-.beta.-estradiol in an acrylate polymer with the addition of crystallization inhibitors and tackifying resins. The systems contain swelling substances for protection against premature loss of adhesiveness.
However, with many active substances there is a possibility to add so-called enhancers (penetration enhancers) to the TTS during the production. These are additives, which are generally liquid and which enhance the resorption properties of the human skin and thus permit resorption from a sufficiently small TTS area. Particularly highly volatile enhancers, such as ethanol, which is used for example for the active substance 17-.beta.-estradiol, present problems of excessive softening of the adhesive layers of the TTS and, above all, make further space-consuming compartments necessary, which render the TTS unacceptably thick.
Furthermore, every additional non-polymeric additive involves a danger of intolerance to the skin, possibly also of sensitization.
However, when adding certain, less volatile enhancers (e.g. glycerol ester, cyclic amids, eucalyptol), which are, however, mostly less active, it is possible to produce matrix systems that contain the active substance and the resorption-enhancing component in one or more monolithic layers.
U.S. Pat. No. 4,863,738 is one of many examples claiming the application of active substances, e.g. 17-.beta.-estradiol together with a particular enhancer (in this case glyceryl mono-oleate) in any desired TTS matrix and in any desired concentration.
Unfortunately, according to the state of the art, with such TTS a satisfactory therapy cannot be achieved either, since either the selected enhancers are too poorly tolerated by the skin, or the systems have an unacceptable large area owing to the still insufficient flow through the skin.
Another (theoretic) possibility to increase the active substance flow through the skin is to dissolve greater amounts of the active substance in the TTS as a molecular dispersion than corresponds to the saturation solubility. As the degree of oversaturation of such systems increases, the speed of the permeation through the skin increases accordingly. As such physical conditions are, however, thermodynamically unstable, pharmaceutic products of this kind cannot be stored. Within months or at the latest years, a spontaneous, unpredictable precipitation of active substance particles occurs, so that the flow rate through the skin gradually falls down to the saturation flow level, and thus a great part of the initially present therapeutic activity is lost.